Optimal management of PAD: Practical tips and real-world experience

Despite its life- and limb-threatening complications and poor prognosis, peripheral arterial disease (PAD) is often underdiagnosed and undertreated. At a Bayer-sponsored webinar, Professor Bryan Yan and Dr Guang-Ming Tan of the Division of Cardiology, Department of Medicine and Therapeutics, Chinese University of Hong Kong, and Dr Esmond Fong of the Division of Cardiology, Department of Medicine, Queen Elizabeth Hospital, Hong Kong, provided insights into current PAD management strategies and shared their clinical experience in using rivaroxaban, a guideline-recommended antithromobotic agent, in patients with PAD.

Timely diagnosis of PAD: An evidence-based approach
“PAD is grossly underdiagnosed and undertreated,” said Yan. “A significant proportion of patients with symptomatic atherosclerosis have polyvascular disease. Many patients with coronary artery disease [CAD] we see in daily practice may have overlapping yet undiagnosed atherosclerotic diseases, such as PAD or cerebrovascular disease.” [Eur Heart J Suppl 2012;14:A43-A44; JAMA 2006;295:180-189]

The international REACH registry revealed that patients with PAD had higher 3-year rates of myocardial infarction (MI)/stroke/death/rehospitalization than those with CAD or cerebrovascular disease alone, and almost 10 percent of PAD patients progressed to develop polyvascular disease over 3 years. [Eur Heart J 2009;30:2318-2326] “Early diagnosis and treatment can slow the progression of atherosclerosis and lower the risk of MI and stroke,” added Yan.

Diagnosis of PAD requires comprehensive assessment of medical history and symptoms, such as claudication and ischaemic pain, as well as physical examination to identify lower extremity pulse abnormalities and nonhealing wounds. [J Atheroscler Thromb 2020;27:809-907; J Am Coll Cardiol 2017;69:e71-e126] Asking patients a single claudication question of whether they have pain in either leg on walking is a simple first-step screening tool for PAD with similar performance as traditional questionnaires. [PLoS One 2019;14:e0224608; Tan GM, 2022]

“For cardiologists, identification of PAD patients should begin with a single claudication question,” commented Tan. “Simple bedside examination for peripheral pulses/bruits in addition to standard cardiac tests should follow, which altogether should take about 5 minutes to perform.”

To confirm the diagnosis of PAD, the ankle-brachial index (ABI) is a noninvasive first-line test. (Table) Additional imaging tests such as Duplex ultrasound (DUS), CT angiography (CTA) or magnetic resonance angiography (MRA) are also recommended for patients who are considered for revascularization. (Figure 1) [J Am Coll Cardiol 2017;69:e71-e126]

Net clinical benefit of rivaroxaban in PAD: Trial findings
Antithrombotic therapy is recommended for all symptomatic PAD patients. However, decision-making should be individualized and based on the net clinical benefit of therapies. [Vasa 2019;48:1-79; JAMA 2018;319:2329-2330]

In a subgroup analysis of the CHARISMA trial involving 3,096 PAD patients, dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel did not reduce the risk of major adverse cardiovascular events (MACE) (hazard ratio [HR], 0.85; 95 percent confidence interval [CI], 0.66–1.08; p=0.18) and was associated with an increased risk of minor bleeding (odds ratio [OR], 1.99; 95 percent CI, 1.69–2.34; p<0.001) vs aspirin monotherapy. [Eur Heart J 2009;30:192-201] Among 1,143 PAD patients with prior MI in the PEGASUS-TIMI 54 trial, aspirin plus ticagrelor was associated with a nonsignificant reduction in MACE (HR, 0.75; 95 percent CI, 0.55–1.01) and increased Thrombolysis in Myocardial Infarction (TIMI) major bleeding (HR, 1.32; 95 percent CI, 0.41–4.29) vs aspirin alone. [J Am Coll Cardiol 2016;67:2719-2728]

In the COMPASS trial in 7,470 PAD patients, rivaroxaban 2.5 mg BID plus aspirin 100 mg QD led to significant reductions in MACE (HR, 0.72; 95 percent CI, 0.57–0.90; p=0.0047) and major adverse limb events including amputation (HR, 0.54; 95 percent CI, 0.35–0.82; p=0.0037) vs aspirin alone. The composite net clinical benefit outcome of cardiovascular (CV) death, MI, stroke, and fatal or critical organ bleeding was observed in 6 percent vs 7 percent of the patients (HR, 0.75; 95 percent CI, 0.60–0.94; p=0.011). [Lancet 2018;391:219-229]

The VOYAGER PAD trial (n=6,547) supports the use of rivaroxaban plus aspirin in PAD patients undergoing lower extremity revascularization, showing consistent efficacy in the primary composite outcome of acute limb ischaemia, major amputation of a vascular cause, MI, ischaemic stroke, or CV death vs aspirin regardless of concomitant clopidogrel use (with clopidogrel: HR, 0.85; 95 percent CI, 0.71–1.01; without clopidogrel: HR, 0.86; 95 percent CI, 0.73–1.01; p_interaction=0.92). Results for the principal safety outcome of TIMI major bleeding were also consistent regardless of concomitant clopidogrel use (with clopidogrel: HR, 1.33; 95 percent CI, 0.78–2.26; without clopidogrel: HR, 1.55; 95 percent CI, 0.88–2.72; p_interaction=0.71). (Figure 2) [Circulation 2020;142:2219-2230; Hiatt WR, at al, ACC 2020]

Real-world application of antithrombotic therapy in PAD should be individualized, taking into account the balance of ischaemic events and bleeding to achieve optimal clinical outcomes. [Am Heart J 2019;218:100-109] For symptomatic or revascularized PAD patients at increased risk of ischaemic events (eg, those with diabetes, chronic kidney disease [CKD], chronic heart failure [CHF]) but at low risk of bleeding, dual pathway inhibition with aspirin plus rivaroxaban may be a favourable approach. [Am Heart J 2019;218:100-109]

“COMPASS and VOYAGER PAD showed that aspirin plus rivaroxaban improved CV and limb outcomes with a favourable benefit-to-risk ratio,” concluded Fong. “Balancing ischaemic and bleeding risk for the individual patient remains the key management goal.”